The present invention relates to methods for treating wounds, burns, or dermatological damage by administering topical compositions containing selegiline and/or desmethylselegiline.
A. Free Radicals
Free radicals are molecules with one or more unpaired electrons in their outer orbitals. The presence of these electrons together with the tendency of molecules to seek the lowest stable energy state causes free radicals to be highly reactive and generally short lived. Among the free radicals commonly found in vivo are oxygen, the superoxide anion and the hydroxyl radical. These are typically referred to as xe2x80x9coxidantsxe2x80x9d and are often the result of cascades in which electrons are passed from molecule to molecule.
B. Injuries and Free Radical Damage
Injuries such as wounds and burns generate free radicals that have both local and systemic effects. Locally, free radicals have been implicated in both tissue ischemia (Granger, et al., Gastroenterology 81:22-29 (1981); Parks, et al., Gastroenterology 82:9-15 (1982)) and reperfusion injuries (Schiller, et al., Critical Care Med. 21:S92-S100 (1993)). Systemically, burns often cause dysfunction of the heart, lungs and liver. Researchers have found that burn healing is improved when lipid peroxidation (typically caused by the action of free radicals) is reduced (LaLonde, et al., J. Burns Care and Rehabilitation 17:379-383 (1996)).
C. Photodamage
Exposure of skin to electromagnetic radiation in the ultraviolet and visible portions of the spectrum and ionizing radiation may result in damage to both the proteins and the DNA in skin cells. Such xe2x80x9cphotodamagexe2x80x9d has been correlated with the induction of non-melanoma skin cancer, immune function suppression and photoaging.
Exposure of skin to ultraviolet and ionizing radiation and the concomitant pathobiologies have been linked to the generation of oxidants as well as to a reduction in anti-oxidant levels and activity (Stewart, et al., J. Inv. Dermatol. 106:1086-1089 (1996); Darr, et al., Brit. J. Dermatol. 127:247-253 (1992)). Specifically, research has shown that there is a reduction in epidermal superoxide dysmutase activity and in the levels of vitamin C and vitamin E after exposure to UVB radiation. Elimination of oxidants (e.g., by application of exogenous anti-oxidants) or prevention of oxidant production (e.g., by reduction of exposure to ionizing radiation) can alleviate or prevent dermatological damage. The adverse effects of ionizing radiation include edema, vasodilation, lymphocytic and neutrophilic infiltration in the dermis, dyskeratotic keratinocytes and spongiosis of the epidermis.
D. Use of Anti-Oxidants to Detoxify Free Radicals
A number of different strategies have been used in attempting to prevent or reduce free radical damage. Endogenous anti-oxidants, e.g., superoxide dysmutase, catalase or glutathione peroxidase, may be used to protect cell membranes and agents such as ascorbic acid and glutathione may be used to protect cytosols. Other anti-oxidants, such as alpha-tocopherol and tretinoin, have also been used to ameliorate the effect of free radicals.
Administration of superoxide dysmutase, post-ischemia prevents the increased capillary permeability which accompanies reperfusion injuries (Granger, et al., Gastroenterology 81:22-29 (1981)) and the ablation of free radical generation prior to, and at the time of, reperfusion may prevent or lessen the severity of multiple system organ failure syndrome (Schiller, et al., Critical Care Med. 21:S92-S100 (1993)). Stewart, et al. have shown that UVB-induced DNA damage in human keratinocytes is attenuated by supplementing culture medium surrounding the cells with anti-oxidants such as vitamin C, selenite, or a water-soluble vitamin E analog (J. Inv. Dermatol. 106:1086-1089 (1996)).
E. Selegiline and Desmethylselegiline
Monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) are enzymes found in both in the central nervous system and in peripheral tissues. MAO-A and MAO-B catalyze the oxidative deamination of primary amines, including neuroactive and vasoactive amines, resulting in the formation of toxic free radical species and free radical-generating cascades. Selegiline is a potent and selective inhibitor of monoamine oxidase B and has been reported to have an action in protecting or rescuing neurons of the central nervous system (Knoll, Mount Sinai J. Med. 55:67-74 (1988)). Although the exact mechanism by which selegiline causes its effects is not known, there is evidence suggesting that it may provide neuroprotection or neuronal rescue by reducing oxidative damage caused by monoamine oxidase and/or other oxidants (Jenner, et al., Neurology 47:S162-S170 (1996)). In this regard, selegiline has been shown to increase the activity of the endogenous anti-oxidants superoxide dysmutase, catalase and glutathione peroxidase (Id.).
Desmethylselegiline, one of the metabolites of selegiline, exhibits reduced MAO-B inhibitory activity in comparison to selegiline and its activity with respect to the inhibition of MAO-A is decreased to an even greater extent. Thus, it is expected that desmethylselegiline should produce selegiline-like neuroprotective effects with a decreased risk of side effects associated with MAO-A inhibition.
Although selegiline has been used to treat Parkinson""s disease, its use as a treatment for injuries, such as burns and wounds, and for alleviating dermatological damage, such as photodamage, has not been known heretofore. The present invention is directed to methods which rely upon the administration of selegiline or desmethylselegiline to speed the healing and reduce the complications associated with these conditions.
The present invention is based upon the discovery that compositions comprising selegiline and/or desmethylselegiline can be used in the treatment of wounds, burns and photodamaged skin. In the case of burns and wounds, compositions should be administered for a duration sufficient to promote epithelization. In the case of photodamaged skin, the composition should be administered for a duration sufficient to promote healing, as evidenced by a reduction in one or more of the symptoms associated with photodamaged skin. These symptoms include edema, vasodilation, lymphocytic and neutrophilic infiltration in the dermis, dyskeratotic keratinocytes and spongiosis of the epidermis.
Although the invention encompasses administration by any route, delivery by means of a topical composition containing between 1xc3x9710xe2x88x9211 moles/liter and 1xc3x9710xc3x973 moles/liter of selegiline and/or desmethylselegiline is preferred. Topical compositions may be delivered by means of a spray, patch, salve, cream, lotion or gel. As used herein, the term xe2x80x9cdesmethylselegilinexe2x80x9d refers to either the R(xe2x88x92) enantiomeric form of the drug, the S(+) enantiomeric form of the drug, or a racemic mixture of the two. In carrying out the present methods, the R(xe2x88x92) enantiomer may be used in the substantial absence of the S(+) enantiomer or vice versa. An enantiomer is substantially absent if it constitutes less than 10% of the combined desmethylselegiline enantiomers. Compositions may contain water, suspending agents, thickeners, humectants, preservatives, emollients, emulsifiers and film formers. They may be applied either directly to the skin of a patient or they may be applied as part of a patch.
Although not preferred, non-topical routes of administration are compatible with the present invention and may be used. The dosage of selegiline or desmethylselegiline when used non-orally should be at least 0.015 mg per kg body weight, calculated on the basis of the free secondary amine, with progressively higher doses being employed depending upon the route of administration and the subsequent response to therapy. Typically, the daily non-oral dose will be about 0.10 mg/kg and may extend to about 1.0 mg/kg (all such doses again being calculated on the basis of the free secondary amine).
In the following description, reference will be made to various methodologies well known to those skilled in the art of medicine and pharmacology. Such methodologies are described in standard reference works setting forth the general principles of these disciplines. Unless otherwise indicated, the descriptions apply to selegiline, and all enantiomeric forms of desmethylselegiline.
Dosage
The optimal daily dose of selegiline and/or desmethylselegiline useful for the purposes of the present invention may be determined by methods known in the art based upon clinical conditions such as the severity of the injury, the condition of the subject to whom treatment is being given, the desired therapeutic response and the concomitant therapies being administered to the patient or animal. Ordinarily, however, it is expected that the attending physician or veterinarian will apply a topical composition containing a concentration of selegiline and/or desmethylselegiline between 1xc3x9710xe2x88x9211 moles/liter and 1xc3x9710xe2x88x923 moles/liter, preferably between 1xc3x9710xe2x88x929 moles/liter and 1xc3x9710xe2x88x923 moles/liter. Sufficient composition should be administered to completely cover the damaged area on the individual""s skin.
If the physician chooses non-oral routes of administration, at least 0.015 mg/kg of selegiline and/or desmethylselegiline should be administered daily with the more typical dosage being about 0.10 mg/kg. The daily dosage may be increased up to about 1.0 mg/kg. In all cases, doses are calculated on the basis of the free secondary amine form of the agent being administered. These guidelines further require that the actual dosage be carefully titrated by the attending physician or veterinarian depending upon the age, weight, clinical condition and observed response of the individual being treated.
Topical compositions can be applied several times during the day to wounded, burned or photodamaged skin. Similarly, daily dosages of non-oral preparations may be administered in a single or multiple dosage regiment. In addition, dosage forms permitting the continuous release of active agent, e.g., a transdermal patch, may be used for delivering drug.
Dosage Forms Route of Administration
As noted above, topical administration and topical dosage forms are generally preferred for the present methods. However, any of the numerous dosage forms described in the literature for the administration for selegiline may be used and may include desmethylselegiline as desired. For example, U.S. Pat. No. 4,812,481 discloses the use of selegiline, in combination with amantadine, in oral, pectoral, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous formulations. Dosage forms for selegiline having an outer wall with one or more pores in the wall impermeable to selegiline but permeable to external fluids have been described. This dosage form may have applicability for oral, sublingual, or buccal administration. Similarly, a variety of selegiline compositions, including tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil suspensions, solutions and emulsions have been described. Further disclosed are selegiline-containing sustained release (long acting) formulations and devices.
Topical dosage forms may be prepared according to conventional techniques with creams being generally preferred. The topical cream may be a cosmetically elegant oil in water, cream/lotion/emulsion, containing the desired specified concentration of selegiline and/or desmethylselegiline. Such moisturizing cream formulations may contain a vehicle, a buffer system to maintain the vehicle at an appropriate pH, and an acceptable antimicrobial preservative system. The cream may further contain thickeners, humectants, emollients, emulsifiers and film formers. Methods for preparing appropriate formulations are well known in the art (see e.g., Remington""s Pharmaceutical Sciences, 16th ed., A. Oslo. ed., Easton Pa. (1980)).
Transdermal dosage forms can be prepared utilizing a variety of techniques that have been described in the art. Examples may be found in U.S. Pat. Nos. 4,861,800; 4,868,218; 5,128,145; 5,190,763; and 5,242,950; and in foreign patent documents EP-A 404807; EP-A 509761; and EP-A 593807. A monolithic patch structure can be utilized in which drug is directly incorporated into the adhesive and this mixture is cast onto a backing sheet. EP-A 593807 describes a composition in which selegiline is administered as an acid addition salt by incorporating it into a multi layer patch which promotes a conversion of the salt into the free base form of selegiline. One can also employ a device using a lyotropic liquid crystalline composition in which, for example, 5-15% of selegiline is combined with a mixture of liquid and solid polyethylene glycols, a polymer and a non-ionic surfactant, optionally with the addition of propylene glycol and an emulsifying agent. Further details on the preparation of such transdermal formulations are found in the patent literature.
Buccal and sublingual dosage forms of selegiline and/or desmethylselegiline may be prepared utilizing techniques described in, for example, U.S. Pat. Nos. 5,192,550; 5,221,536; 5,266,332; 5,057,321; 5,446,070; or 5,354,885.
Chemical Form of Selegiline or Desmethylselegiline
The present invention is not limited to any particular form of selegiline and/or desmethylselegiline and drugs may be used either as free bases or as pharmaceutically acceptable acid addition salts. In the latter case, the hydrochloride salt is generally preferred. However, other salts derived from organic and inorganic acids may also be used.
Manner of Treatment
The methods disclosed herein may be used for both human and nonhuman subjects. With regard to the latter, the methods are particularly, but not exclusively, directed to domesticated mammals such as canine and feline species.
In the case of wounds and burns, treatment by administration of selegiline and/or desmethylselegiline should be continued until epithelialization is complete. For dermatological damage, treatment should be continued until the related symptoms, such as edema, vasodilation, lymphocytic and neutrophilic infiltration or spongiosis of the epidermis, subside. The drugs may be either administered at regular intervals (e.g., twice a day) or in an essentially continuous manner (e.g. via a transdermal patch).